ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 7-7 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Emmanuel S. Antonarakis ◽  
Charles J. Ryan ◽  
William R. Berry ◽  
Neal Shore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Phase I ◽  
Phase Ii ◽  
Nuclear Translocation ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Psa Response ◽  
Psa Progression

7 Background: ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC (high risk non-metastatic CRPC, metastatic treatment-naïve CRPC, and progressive disease after abiraterone acetate). Preliminary results for the cohort of patients with high-risk non-metastatic CRPC are presented here. Methods: All patients had CRPC, no radiographic evidence of metastases (pelvic lymph nodes <3 cm below the iliac bifurcation were allowed), and high risk for disease progression based on PSA value ≥ 8 ng/mL within 3 months of enrollment and/or PSA doubling time ≤ 10 months. Patients received ARN-509 at the recommended Phase II dose of 240 mg/day, previously established in Phase I (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria. Secondary endpoints included safety, time to PSA progression and 1-year metastasis-free survival. PSA assessments were collected every 4 weeks and tumor scans were performed every 16 weeks. Results: Forty-seven patients were enrolled between November 2011 and May 2012. The median age was 71 years (range 51 to 88) and at baseline, patients presented with ECOG performance status 0 (77%), Gleason Score 8-10 (32%), and median PSA of 10.7 ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 20 weeks, three patients discontinued the study. The most common treatment-related adverse events (AE) were fatigue (30%), diarrhea (28%), nausea (17%), rash (13%), and abdominal pain (11%). The incidence of Grade 3 AEs was 6.4%, and no seizures have been observed to date. The 12-week PSA response was 91% and the time to PSA progression has not been reached. Conclusions: In men with high-risk non-metastatic CRPC, ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA response rates. Clinical trial information: NCT01171898.

Determining biomarkers of response to docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating cell-free tumor DNA (ctDNA).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 260-260
Author(s):  
Daniel Khalaf ◽  
Cameron Herberts ◽  
Gillian Vandekerkhove ◽  
Matti Annala ◽  
Kevin Beja ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Pten Loss ◽  
Discernible Effect ◽  
Pten Deletion ◽  
Psa Response ◽  
Psa Progression ◽  
Ctdna Analysis

260 Background: Docetaxel is associated with improved outcomes for mCRPC. There are currently no predictive molecular biomarkers for docetaxel to assist with patient selection. Methods: Patients commencing docetaxel for mCRPC between November 2015 and August 2017 were enrolled on a prospective cohort study evaluating circulating biomarkers. A plasma sample for ctDNA analysis was collected before initiation of docetaxel. Targeted sequencing of 73 prostate cancer-relevant genes was performed on leukocyte DNA (germline) and plasma cell-free DNA. Patient records were reviewed for baseline clinical characteristics, PSA response (≥ 50% decline from baseline), and time to PSA progression (TTPP) (PCWG3 criteria). Results: There were 33 patients enrolled; all patients had received prior abiraterone or enzalutamide and none had received prior taxanes. At baseline, the median age was 69.9 years, 30.3% had ECOG performance status 2, 66.7% had bone metastasis and 9.1% had liver metastases. The PSA response rate (RR) was 39.4% and 33.3% had a TTPP less than 3 months. 82% of patients had a ctDNA fraction >5%. Deleterious BRCA2 or ATM defects were present in 12.1% (4/33) of patients (3 somatic and 1 germline). TP53 alterations were identified in 39.4% (13/33), RB1 loss in 21.2% (7/33), PTEN loss in 21.2% (7/33), and Androgen Receptor (AR) amplification in 42.2% (14/33). PTEN deletion was associated with a trend toward inferior RR and TP53 had no discernible effect on PSA RR (Table). BRCA2/ATM defects were associated with a trend toward a lower rate of PSA progression within 3 months (Table). Conclusions: In this preliminary analysis, TP53 alterations had no discernible effect on efficacy of docetaxel chemotherapy. Accrual is ongoing in order to further clarify whether there is an association between PTEN, RB1, AR and BRCA2/ATM alterations and benefit from docetaxel. [Table: see text]

Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5066-5066
Author(s):  
Mark T. Fleming ◽  
Dana E. Rathkopf ◽  
Jackie Gibbons ◽  
Amy C. Peterson ◽  
Alison Hannah ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Phase I ◽  
Phase I Study ◽  
Performance Status ◽  
Safety Data ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Combination Methods

5066 Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

Enzalutamide in combination with docetaxel in men with prostate cancer (PC): Preliminary results from a phase I study.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 63-63 ◽  
Author(s):  
Mark T. Fleming ◽  
Dana E. Rathkopf ◽  
Jackie Gibbons ◽  
Amy C. Peterson ◽  
Alison Hannah ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nuclear Translocation ◽  
Performance Status ◽  
Safety Data ◽  
Phase Iii ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Current Standard ◽  
Ecog Performance Status ◽  
To Receive

63 Background: Enzalutamide (ENZA), a novel oral androgen receptor (AR) inhibitor, inhibits AR signaling via inhibition of androgen binding to the AR, AR nuclear translocation, and nuclear AR-DNA binding. ENZA demonstrated a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (Scher et al, NEJM 2012; 367:1187). A Phase III study in men with progressive chemotherapy-naïve disease (PREVAIL), is ongoing. Docetaxel (DOC) is the current standard first-line chemotherapy for mCRPC. CYP3A4, which plays a role in DOC clearance, is induced by ENZA. Patients (pts) eligible to receive DOC may benefit from continued AR inhibition with ENZA, provided the combination is well tolerated with no unacceptable drug-drug interactions. Methods: This study evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks, with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: As of 21 Sept. 2012, 22 pts have been enrolled, 3 did not complete both C1 and C2; PK and C1 and C2 safety data are currently available from 15 pts reported here. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone. Conclusions: This is the first evaluation of ENZA given in combination with DOC.In mCRPC pts ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 18-18 ◽  
Author(s):  
Bertrand Tombal ◽  
Michael Borre ◽  
Per Rathenborg ◽  
Patrick Werbrouck ◽  
Axel Heidenreich ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Phase Ii ◽  
Nuclear Translocation ◽  
Phase Ii Study ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Hot Flush ◽  
Study Results ◽  
Psa Response

18 Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor–binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III studies that exclusively enrolled patients with CRPC receiving androgen deprivation therapy (ie, testosterone (T) levels ≤50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients who had never received hormone therapy; presenting with non-castrate T levels (≥230 ng/dL). Methods: This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint was PSA response (>80% decrease at wk 25). Secondary endpoints included changes in endocrine levels and safety/tolerability. Results: Among 67 men enrolled, the median (range) age was 73 (48, 86) y; 39% had metastases; 36% and 24% had undergone prostatectomy or radiotherapy before study entry. The PSA response rate (>80% PSA decline at wk 25) was 93%, with a median (range) decrease of −99% (−100, −57) at wk 25. Serum T and estrogen levels increased by a median (range) of 113% (−32, 300) and 58% (−49, 321) at wk 25, respectively, compared with baseline. 82% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (36%), fatigue (34%), and hot flush (18%). 7% of men experienced SAEs; none were drug-related. Conclusions: ENZA monotherapy (160 mg) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Endocrine level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT01302041.

Phase II study of cabazitaxel (CAB) plus enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 86-86
Author(s):  
Julie Nicole Graff ◽  
Heather H. Cheng ◽  
Jacqueline Vuky ◽  
Joshi J. Alumkal ◽  
Dustin Kreitner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Failure To Thrive ◽  
Castration Resistant Prostate Cancer ◽  
Eligibility Criteria ◽  
Psa Response ◽  
Pre Treatment ◽  
Grade 3

86 Background: There are six agents that improve survival in mCRPC, each administered as a single agent. Combinations of agents with distinct mechanisms of action have the potential to improve outcomes. Methods: We performed a multi-institution phase I/II study to examine safety and efficacy of CAB plus ENZ with mandatory granulocyte-colony stimulating factor support in mCRPC. Results: A sample size of 3 to 12 subjects for the phase I portion and 33 for the phase II portion provided 82% power to detect PSA response rate (decrease ≥90%) of 50% compared to the null hypothesis of 24%. The main eligibility criteria allowed prior abiraterone/prednisone (AAP) and docetaxel (in the metastatic hormone sensitive setting). Baseline characteristics: median age 69 years (47 - 82), median PSA 20.2 ng/dl (0.2 - 966.3); 7 subjects had visceral disease, 10 received prior AAP, and 8 received prior docetaxel. In the phase I portion, there were no dose limiting toxicities using CAB 25 mg/m2 IV Q3wks up to 10 cycles and ENZ 160 mg PO QD, hence this dosing was used for the phase II portion. 33 men with mCRPC were treated with CAB plus ENZ in the phase II arm. PSA response rates are listed in Table. Prior exposure to AAP decreased PSA response, but subjects who had prior AAP also had higher pre-treatment PSA. There were no treatment related deaths. Dose reduction of CAB to 20 mg/m2 was needed in 7 subjects. Over the course of the study, 14 Grade 3 adverse events occurred that were deemed possibly related to treatment: fatigue (n=2, 6%), febrile neutropenia (n=2, 6%), leukopenia (n=2, 6%), thrombocytopenia (n=2, 6%), anemia (n=1, 3%), hypertension (n=1, 3%), leukocytosis (n=2, 6%), fracture (n=1, 3%), failure to thrive (n=1, 3%). Conclusions: CAB plus ENZ was tolerable and associated with promising anti-tumor activity, particularly in abiraterone-naïve subjects. Further evaluation of this regimen is warranted. This project was managed by the Prostate Cancer Clinical Trials Consortium and funded by Astellas Inc. and Sanofi. Clinical trial information: NCT02522715. [Table: see text]

Durable radiologic and clinical disease stability beyond PSA progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4553-4553
Author(s):  
Diletta Bianchini ◽  
Shahneen Kaur Sandhu ◽  
Amy Mulick Cassidy ◽  
Andrea Zivi ◽  
Janusz Mezynski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Clinical Disease ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Ecog Performance Status ◽  
Conversion Rates ◽  
Psa Progression

4553 Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC. CTC conversion from CTC ≥ 5 to CTC < 5 with treatment predicts for improved overall survival in mCRPC. We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA. Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained at predefined time points during these studies. Radiological and PSA progression were defined by standard Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain, skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions: Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond PSA and radiological progression can impact outcome.

A randomized phase II trial of dexamethasone versus prednisolone as secondary hormonal therapy in CRPC.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 123-123 ◽  
Author(s):  
Ramachandran Venkitaraman ◽  
Karen Thomas ◽  
Vedang Murthy ◽  
Ruth Woode-Amissah ◽  
David Paul Dearnaley ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Active Agent ◽  
Hormonal Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Psa Response ◽  
Psa Progression

123 Background: Dexamethasone and prednisolone are glucocorticosteroids used as second line hormonal treatment for castration refractory prostate cancer (CRPC). The biochemical response rates in cohort studies suggest that dexamethasone may be the more active agent. We conducted an open label, randomised phase II trial of dexamethasone versus prednisolone. Methods: Patients with castration resistant prostate cancer with progressive disease on androgen deprivation therapy were eligible. They were randomized to receive either prednisolone 10mg daily or dexamethasone 0.5mg daily. The main endpoint was confirmed PSA response rate according to the PSA Working Group 2 criteria. Patients with PSA progression on prednisolone crossed over to dexamethasone. Secondary endpoints included time to PSA progression, radiologic response rate using RECIST criteria, and safety. Results: Seventy-five patients were randomized. Confirmed PSA response was achieved in 12/39 patients (31%) on dexamethasone compared to 6/36 (17%) on prednisolone (p = 0.153). Median time to PSA progression was 9.7 months on dexamethasone compared to 5.1 months on prednisolone (HR 1.57, 95% CI 0.90 -2.75). In 43 patients with measurable disease, the response rate by RECIST criteria was 15% and 6% for dexamethasone and prednisolone, respectively (p = 0.606). Clinically significant toxicities were rare. Of 23 patients who crossed over at progression on prednisolone to dexamethasone, 19 patients were evaluable for PSA response. Seven of the 19 patients (37%) had a confirmed PSA response to dexamethasone after progression on prednisolone. Conclusions: The data are consistent with the hypothesis that dexamethasone is more active than prednisolone in the treatment of CRPC. In the absence of definitive, larger trials, dexamethasone should be used in preference to prednisolone in this setting. Clinical trial information: 2005-006018-16.

A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 179-179
Author(s):  
Deepak Kilari ◽  
Elizabeth A. Guancial ◽  
Deepak M. Sahasrabudhe ◽  
Kathryn A. Bylow ◽  
John D. Burfeind ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Study Endpoint ◽  
Primary Study ◽  
Clinical Activity ◽  
Ecog Performance Status

179 Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In prior studies, peripheral androgen blockade with bicalutamide and Fin was better tolerated but less efficacious than ADT in HNSPCa. The potential syngerism of Enz (a potent antiandrogen) and Dut/Fin (5-a reductase inhibitors for conversion of testosterone [T] to dihydrotestosterone [DHT]) provided the rationale for this Phase II study that examined the clinical efficacy and safety of Enz with Dut/Fin in men > 65 years with HNSPCa. Methods: Eligible patients were > 65 years (y) ; at a high risk of AE from ADT by comprehensive geriatric assessment or treating physicians; had metastatic (M1) or biochemical recurrent (M0) HNSPCa with a PSA doubling time < 9 months; and had T > 50ng/dl. They received Enz (160mg daily) and Dut (0.5mg daily) or Fin (5mg daily) until disease progression according to the Prostate Cancer Working Group 2 guidelines. The primary study endpoint is time to PSA progression. The secondary endpoints are time to PSA nadir and treatment-related AEs. Results: As of July 31, 2016, 24 patients were screened (3 ineligible) and 21 were enrolled with a median follow-up of 31 weeks (7-79). Median age at enrollment was 79.5 y (66-94) and 14 %, 72% and 14% had ECOG performance status of 0, 1, and 2, respectively. 57% (n = 12) had M0 and 43% (n = 9) had M1 HNSPCa, with 18%, 62%, 5%, and 10% having Gleason 6, 7, 8, and 9 disease, respectively (5% with unkown Gleason sum). The median PSA at enrollment was 12 ng/ml (2-102). The median time to 90% PSA decline after treatment initiation was 7 weeks (7-20) and 92% achieved 80% DHT decline in 9 months. At the time of analysis, all patients had ongoing PSA decline of > 90% without radiographic evidence of disease progression. Common Grade 1 AEs included gynecomastia (28%), fatigue (28%), hot flashes (19%) and paresthesias (15%). One patient withdrew from the study due to Grade 2 paresthesia. None had Grade 3 or 4 treatment-related AEs. One patient died due to colitis unrelated to study treatments. Conclusions: Enz with Dut/Fin appears to have clinical activity for older patients with M0 and M1 HNSPCa with acceptable side effects. Clinical trial information: NCT02213107.

Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5012-5012 ◽  
Author(s):  
K. N. Chi ◽  
S. J. Hotte ◽  
E. Yu ◽  
D. Tu ◽  
B. Eigl ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Cancer Society ◽  
Best Response ◽  
Randomized Phase Ii ◽  
Psa Response ◽  
Visceral Metastases

5012 Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2'-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of <640 mg. Methods: Pts with CRPC and chemo-naive received docetaxel (DOC) 75mg/m2 q3w + OGX 640mg IV weekly + prednisone (Arm A) or DOC + prednisone (Arm B) in a single stage randomized phase II design. Primary endpoint was PSA response rate (RR). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Planned sample size was 40/arm: Arm A the hypotheses (PSA RR<40% vs. >60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI<13% if PSA RR=40%. Results: 82 pts (41 Arm A, 41 Arm B) were randomized from 09/05–12/06. At this analysis time, all pts are off therapy and 49 have died. One pt was ineligible but included in ITT survival analysis. Baseline characteristics were similar: median age 69 (49–87), PSA >100 μg/L in 51%, Hgb ≥100 g/L in 98%, alk phos >ULN in 44%, LDH >ULN in 36%, ECOG performance status (PS) 0:1 in 51%:49%, bone/lymph node/visceral metastases in 69%/50%/28%. Median cycles for Arm A and B was 9 and 7. Adverse events associated with OGX included fatigue, fever, rigors, diarrhea and rash. Mean serum clusterin change on day 1 cycle 2 was -18% in Arm A and +8% in Arm B (p = 0.0005). PSA RR was 58% (Arm A) and 54% (Arm B). PSA declines at 12 weeks of any/>30%/>50% was observed in 87%/65%/45% (Arm A) and 68%/58%/34% (Arm B). PSA/objective disease progression as best response occurred in 0%/4% (Arm A), and 3%/17% (Arm B). PFS for Arms A and B was 7.3 (5.3–8.8) and 6.1 months (3.7–8.6). Median OS for Arms A and B was 27.5 (19.2-∞) and 16.9 months (12.7–26.0) (unadjusted HR = 0.60 [0.34–1.06], p = 0.07). Variables predictive of OS on multivariate analysis: PS 0 vs 1 (p = 0.0002), presence of visceral metastasis (p = 0.006) and treatment assignment (HR = 0.54 [0.29–0.97], p = 0.04). Conclusions: The PSA RR in both arms met criterion for further study. OGX reduced serum clusterin and OS appears superior with DOC/OGX. This combination warrants further evaluation. Supported by a grant from the NCI-Canada/Canadian Cancer Society. [Table: see text]

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